LUPUS 2023.pdf

Anais Brasileiros de Dermatologia 2023;98(3):355---372 Anais Brasileiros de Dermatologia www.anaisdedermatologia.org.b...

Anais Brasileiros de Dermatologia 2023;98(3):355---372 Anais Brasileiros de Dermatologia www.anaisdedermatologia.org.br REVIEW Cutaneous lupus erythematosus: a review of etiopathogenic, clinical, diagnostic and therapeutic aspects! a,∗ a,b Everton Carlos Siviero do Vale , Lucas Campos Garcia a Dermatology Service, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil b Department of Internal Medicine, Faculty of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil Received 27 June 2022; accepted 12 September 2022 Available online 1 March 2023 Abstract Cutaneous lupus erythematosus is an autoimmune disease of varied clinical expres- KEYWORDS sion, which may present as an exclusively cutaneous disease or be one of the multiple Autoimmune manifestations of systemic lupus erythematosus. Its classification includes acute, subacute, diseases; intermittent, chronic and bullous subtypes, which are usually identified based on clinical Lupus erythematosus, features and histopathological and laboratory findings. Other non-specific cutaneous manifes- cutaneous; tations may be associated with systemic lupus erythematosus and are usually related to disease Lupus erythematosus, activity. Environmental, genetic and immunological factors play a role in the pathogenesis of discoid; skin lesions in lupus erythematosus. Recently, considerable progress has been made in elucidat- Lupus erythematosus, ing the mechanisms involved in their development, which allows for foreseeing future targets systemic; for more effective treatments. This review proposes to discuss the main etiopathogenic, clin- Panniculitis, lupus ical, diagnostic and therapeutic aspects of cutaneous lupus erythematosus, aiming to update erythematosus internists and specialists from different areas. © 2023 Sociedade Brasileira de Dermatologia. Published by Elsevier España, S.L.U. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Introduction Lupus erythematosus (LE) is an autoimmune disease with a wide spectrum of clinical expression, ranging from limited ! Study conducted at the Dermatology Service, Hospital das Clíni- cutaneous disease to severe and life-threatening systemic disease due to vital-organ involvement.1 Cutaneous LE (CLE) cas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, presents as an exclusive cutaneous disease or comprises one Brazil. ∗ Corresponding author. of the multiple manifestations of systemic LE (SLE). Skin E-mail: [email protected] (E.C.S. Vale). lesions are present in 70%---80% of SLE cases at some point https://doi.org/10.1016/j.abd.2022.09.005 0365-0596/© 2023 Sociedade Brasileira de Dermatologia. Published by Elsevier España, S.L.U. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).  E.C.S. Vale and L.C. Garcia during their course and may be the initial disease manifes- In 2004, the Düsseldorf classification added another subtype, tation in up to 25% of patients.1 the intermittent CLE (ICLE), which corresponds to tumid LE, Based on the clinical features, histopathological findings, previously considered as a variant of CCLE.3 laboratory findings and duration, LE-specific skin lesions are Some limitations of the aforementioned classifications subdivided into three main subtypes --- acute CLE (ACLE), can be highlighted: a) CLE lesions cannot always be classi- subacute CLE (SCLE) and chronic CLE (CCLE). The identifi- fied as acute, subacute, or chronic, based on histopathology; cation of these subtypes is crucial, as they often occur in b) Interface dermatitis, used as a criterion to define spe- different clinical contexts, with diagnostic, prognostic, and cific CLE lesions, actually lacks specificity, as it may be therapeutic implications.2 present in other conditions, such as dermatomyositis, graft- Exclusive CLE is two to three times more frequent than versus-host disease, and drug reactions; c) Some subtypes SLE, with an annual incidence of 4.3/100,000 in Europe and included as specific, such as tumid LE and lupus panni- the US.1---3 There is a predominance of LE in the female sex, culitis, do not always show interface dermatitis; d) Terms where the incidence of adult SLE is 7 to 15 times higher and, such as acute, subacute or chronic, of a chronological for childhood SLE, 3 to 4 times higher. This female predom- nature, are used to define morphological variations, in inance is less evident in the isolated cutaneous forms of LE, addition to being associated with ill-defined degrees of with a ratio of 4:1, and it is even less significant, with a extension, such as localized or disseminated, related to ratio of 3:1, for discoid LE (DLE), the most common form of topography. For these reasons, in 2010, Lipsker proposed CCLE.2,4 a new classification of LE cutaneous lesions, based on There are also racial differences in the occurrence of clinical characteristics and histopathological findings. Spe- CLE, with a 5.4-fold higher risk of CCLE in African-Americans cific cutaneous lesions, without the obligatory presence of when compared to Caucasians.4 In New Zealand, when com- interface dermatitis, are subdivided into dermo-epidermal, pared to the population of European origin, the indigenous dermal and hypodermic. Non-specific lesions are subdivided Māori population shows a relative risk of 2.47 for the devel- into thrombotic, neutrophilic, or of uncertain pathogenetic opment of all CLE subtypes and 5.96 risks for CCLE.5 nature.11 The peak incidence of SLE occurs in middle age, but it In the absence of a universally accepted classification, occurs later in men.6 Although it also affects children and in 2013, a task force was constituted, consisting of spe- the elderly, exclusive CLE is more common between the ages cialists in the subject, to propose uniformity of diagnostic of 20 and 40 years, with a mean age at onset of 43 years, criteria and classification of CLE, using the Delphi method.12 varying according to the subtype.3 Recently, the validation of the classification criteria for LE skin lesions cause considerable morbidity, mainly due DLE, the most common form of CLE, was presented on an to their chronic nature, the preferential involvement of exclusively clinical basis. The following parameters were exposed parts of the body, and the disfiguring character- included, with different scores being related to skin lesions: istics of their sequelae, which result in significant patient atrophic scar (3 points), location in the pinna (2 points), quality of life impairment.7 preference for head and neck (2 points), dyschromia (1 point), follicular keratosis and corneal plugs (1 point), ery- thematous to violaceous color (1 point). A score of 5 or Classification greater ensures 84% sensitivity and 76% specificity for clas- sification as DLE, and the higher the score, the greater the The diagnostic criteria for classifying SLE are not uniform specificity.13 or universally accepted, with those proposed in 1971 by the American College of Rheumatology (ACR) being the precursors, revised in 1997 (ACR 1997); subsequently, two Etiopathogenesis additional classification systems emerged --- that of the Sys- temic Lupus International Collaborating Clinics (SLICC 2012) SLE and CLE are multifactorial diseases, involving a com- and the joint one between the European League Against plex interaction between genetic load and environmental Rheumatism and the ACR (EULAR/ACR 2019), which are dif- exposures, such as ultraviolet radiation (UVR), drugs, pes- ferentiated and can be compared in Table 1.4,8,9 Each of the ticides, and tobacco.14,15 Epigenetic variations, such as three systems above includes four dermatological findings dysregulation of gene expression, via DNA methylation, as diagnostic criteria for SLE. A current Australian study, or histone modifications, caused by these external fac- which evaluated the performance of different SLE classifi- tors, may trigger the activation of innate and adaptive cations, concluded that the ACR 1997 criteria showed the immunity.4,14 highest specificity; however, the SLICC 2012 provided the Studies on genetic factors involved in CLE are still incipi- highest overall diagnostic accuracy (94.4%), with similar per- ent compared to those described in SLE.16 Despite this fact, formance between patients with early disease.10 genetic polymorphisms, mutations and risk alleles have been The classification proposed by Gilliam & Sontheimer, in identified in different populations of CLE, most of them asso- 1981, was pioneer and differentiates LE cutaneous lesions ciated with innate and adaptive immunity pathways.1,14,17 in specific and nonspecific ones. The specific ones, defined Genes that act in apoptosis, leukocyte migration, type I by the presence of dermo-epidermal interface dermatitis, IFN pathway, complement cascade, antigen presentation, are exclusive to LE, with or without systemic disease. They and antibody production are among the most frequently are subdivided into three categories based on clinical char- affected ones.14,17 Genes that encode the production of acteristics --- ACLE, SCLE and CCLE. The nonspecific lesions pro-inflammatory cytokines are most frequently associated include other cutaneous manifestations associated with SLE. with innate immune pathways in CLE lesions.1 Examples of 356  Anais Brasileiros de Dermatologia 2023;98(3):355---372 Table 1 Classification criteria for systemic lupus erythematosus --- ACR 1997, SLICC 2012 and EULAR/ACR 2019. ACR 19974 SLICC 20128 EULAR/ACR 20199 Entry criteria: none Entry criteria: none Entry criteria: ANA ≥ 1:80 Clinical criteria (=9) Clinical criteria (=11) Clinical criteria (score) Malar rash Acute, subacute CLE or bullous LE Constitutional Discoid rash Chronic CLE (includes tumid CLE) Fever (2) Photosensitivity Oral or nasal ulcers Hematological Oral ulcers Non-cicatricial alopecia Leukopenia (3) Non-erosive arthritis (≥2 joints) Synovitis (≥2 joints) Thrombocytopenia (4) Serositis Serositis Autoimmune hemolysis (4) Pleuritis Pleuritis Neuropsychiatric Pericarditis Pericarditis Delirium (2) Pleural or pericardial effusion Pleural or pericardial effusion Psychosis (3) Renal involvement Kidney disease Seizure (5) Proteinuria > 0.5 g/24 h Proteinuria > 0.5 g/24 h Mucocutaneous Cell casts Hematic casts Non-cicatricial alopecia (2) Neurological alterations Neurological disease Oral ulcers (2) Seizures Seizures Subacute CLE or discoid LE (4) Psychosis Psychosis Acute CLE (6) Hematological alterations Mononeuritis multiplex Serositis Hemolytic anemia Myelitis Pleural or pericardial effusion (5) Leukopenia (